The control of cell function by thyroid hormones is a major unsolved problem in biology. Even the chemical nature of the active iodothyronine hormone is unknown. This proposal represents our initial investigation of the relationship between thyroid hormone receptor binding and hormone action. Recent studies of the intracellular binding of thyroid hormones suggest that there are saturable high affinity binding sites for triiodothyronine in rat liver and kidney nuclei, and kidney cytoplasm. We propose to isolate and characterize intracellular receptors for these hormones in rat liver and kidney subcellular fractions. The binding of iodothyronines to these receptors will be related to hormone action, using the induction of mitochondrial alpha-glycerophosphate dehydrogenase as the initial index of a responsive tissue. Receptors will also be identified in unresponsive tissues and in the liver and kidneys of an unresponsive mammal, the guinea pig, in order to gain further insight into the relationship between receptors and hormone action. Also, a study of the control of mitochondrial function by thyroid hormones will focus on proving the hypothesis that thyroid hormones interact with mitochondrial repressors leading to derepression of nuclear cistrons controlling mitochondrial macromolecular synthesis. Since control mechanisms are disturbed in malignancy, these studies are obviously pertinent to our understanding of the neoplastic process.